Patent GB-1201512-A (GB)
Title: Process for the manufacture of new 11-amino-5,6-dihydro-6-morphanthridones
IPC: A61K31/395
Filed: 1967-12-04
Abstract: 1,201,512. Morphanthridones. CIBA Ltd. 4 Dec., 1967 [5 Dec., 1966; 13 March, 1967; 18 Sept., 1967], No. 55066/67. Heading C2C. Novel compounds of Formula I (in which each of Ph 1  and Ph 2  is a 1,2-phenylene group optionally substituted by C 1-7  alkyl, alkoxy or alkythio, CF 3 , NO 2 , NH 2 , halo or di- (C 1-7 -alkyl) amino; A is a C 1-7  monoaza-, mono-oxa or monothia alkylene radical, the heteroatoms being separated from the N atom by at least two carbon atoms, the N atom of a monoaza-alkylene radical being unsubstituted or substituted by C 1-7  alkyl, hydroxy-C 1-7  alkyl, esterified or etherified hydroxy-C 1-7  alkyl, tertiary amino-alkyl, N-C 1 _ 7  alkyl-monoazaalkylene - imino - C 1-7  alkyl, N - hydroxy (free, etherified or esterified) - C 1-7  alkyl monoazaalkyleneimino, phenyl - C 1-7  alkyl, C 1-7  alkoxycarbonyl or substituted or unsubstituted phenyl and R 3  is H or C 1-7  alkyl) acyl derivatives, iminoethers and quaternary ammonium compounds thereof are prepared by (a) reacting an appropriate 11-esterified hydroxy compound with an appropriate heterocyclic compound; (b) hydrolysing or alcoholizing a compound V in which Y is halo, amino, hydrazino or an aromatic or aliphatic sulphonyloxy group; (c) ring closure of an appropriate 11-N,N-(hydroxyalkyl) 2 - or (esterified hydroxyalkyl) 2 -morphanthridone with R 1 H 2 , where R 1  is O, S or an imino group or (d) reacting an 11-aminomorphanthridone with an appropriate free or esterified dihydroxy compound to effect ring closure; followed where desired by salt formation. Intermediates isolated are 2-chloro-5,6-dihydro - morphanthridin - 6,11 - dione from N- chloro-succinimide and 5,6-dihydro-morphanthridin - 6,11 - dione; 2 - chloro - 11 - hydroxy- 5,6 - dihydro - 6 - morphanthridone by reduction of the first-named intermediate; 2,11-dichloro- 5,6 - dihydro - 6 - morphanthridone by reaction of the last-named intermediate with thionyl chloride; 6,11 - dichloro - morphanthridine from 11 - hydroxy - 5,6 - dihydro - 6 - morphanthridone and phosphorus oxychloride; 6,11-bis- (4 - methyl - piperazino) - morphanthridine by reaction of the last-named intermediate with 1 - methyl - piperazine; 6-chloro-11-(4-methylpiperasino) - morphanthridine from 11 - (4- methyl - piperazino) - 5,6 - dihydro - 6 - morphanthridone and phosphorus oxychloride; 5 - methyl - 5,6 - dihydro - 6 - morphanthridine- 6,11-dione by methylation of 5,6-dihydromorphanthridine - 6,11 - dione; 5 - methyl - 11 - hydroxy - 5,6 - dihydro - 6 - morphanthridone by reduction of the former intermediate; 5-methyl- 11 - chloro - 5,6 - dihydro - 6 - morphanthridone by chlorination of the last-named intermediate with thionyl chloride; 2-chloro-11-(bis-2-hydroxyethylamino) - 5,6 - dihydro - 6 - morphanthridone from 2,11 - dichloro - 5,6 - dihydro - 6 - morphanthridone and di - (2 - hydroxyethyl)- amine; and 11-amino - 2 - chloro - 5,6 - dihydro - 6 - morphanthridone from 2,11-dichloro- 5,6-dihydro-6-morphanthridone and ammonia. Pharmaceutical compositions comprise a compound I together with a suitable carrier and are administered enterally, topically or parenterally. They are effective as antispasmodic and anti-inflammatory agents and are useful in managing and treating gastric irritation and gastric ulcers by reducing gastric secretion.